AIMS: Cerebral inflammation occurs in many neurological disorders, such as stroke and traumatic brain injuries. The first wave of inflammatory responses of glia appears very early but activation of glia is often highly restricted to the region of neuronal death . The progressive enlargement of infarct volume and the breakdown of neuron-glia interactions provide the opportunity for glia to be further activated, and this activation constitutes the second wave of cerebral inflammation. We have previously reported that neurons have the ability to reduce glial activation, and in turn to reduce the extent the second wave of cerebral inflammation. The purpose of this project was to determine the role of neural cell adhesion molecules (NCAM) in mediating the neuronal inhibition of glial activities. ACCOMPLISHMENTS: Activation of glial cells often occurs at the sites of neuronal injury or death, and where there is disruption of communication between glia and neurons. We hypothesized that neural cell adhesion molecules (NCAM) reduce the activation of by immune stimulants. We found that soluble NCAM reduced lipopolysaccharide (LPS)-stimulated nitric oxide (NO) production by cultured glia. A monoclonal antibody that can mimic the functions of NCAM binding to the third immunoglobulin (Ig) domain also reduced LPS-stimulated NO production, whereas another antibody that binds to the second Ig domain of NCAM did not modulate NO production. Using a ten-amino-acid peptide from the third Ig domain of NCAM reduced NO production. Although NCAM is predominantly express on astrocytes, NCAM-like immunoreactivity was detected on LPS-activated microglia with immunocytochemistry, suggesting that NCAM could interact with microglia directly. This study showed that NCAM can modulate LPS-stimulated NO production, most likely via interactions with the third Ig domain. The results suggests that neuron-glia interactions via NCAM could regulate inflammation in the brain. Since NCAM is the major adhesion molecule in neurons, it is possible that NCAM on the surface of neurons form either homophilic binding with NCAM or heterphilic binding with other adhesion molecules of glial cells to mediate the inhibitory influence on glial activities.